Methionine-Derived Metabolites in Apoptosis: Therapeutic Opportunities for Inhibitors of their Metabolism in Chemoresistant Cancer Cells

G.      Quash; G.      Fournet

Abstract

Methionine, in addition to its role in protein synthesis, participates in 3 important cellular functions: as AdoMet in transmethylation; as decarboxylated-AdoMet in aminopropylation; as homocysteine its demethylated form, in transsulphuration. Here we provide evidence from the literature and from our own work for a fourth role for its oxoacid: 4- methylthio-2-oxo-butanoate (MTOB) in apoptosis [28,29]. MTOB enters 2 pathways: (a) transamination by glutaminetransaminase K to methionine[13,14].(b)oxidative decarboxylation by the mitochondrial Branched-Chain-Oxo-Acid- Dehydrogenase-Complex to methional and finally to methylthiopropanoyl CoA (MTPCoA) [26,27]. Some of the methional formed after MTOB decarboxylation leaks into the cytoplasm as free methional [29]. Exogenous methional induces apoptosis in normal and cancer cells in culture [28, 29] but not in those overexpressing the antiapoptotic gene bcl2 [30]. In physiologically-induced apoptosis e.g. trophic factor (IL3) withdrawal, methional leakage is decreased [29] suggesting that MTPCoA is also involved in apoptosis. Both methional and MTPCoA give rise to metabolites that may act as cross-linking agents. In the case of methional, the CH3-S moiety is lost and malondialdehyde (MDA) is formed when methional is subjected to • OH attack [29]. MDA generated in situ from 1,3-propanediol, induces DNA-protein cross-linking [41].With regard to MTPCoA, it is metabolized to malonic semialdehyde CoA (MASACoA) with loss of the CH3-S moiety [48,49 ]. The capacity of MASACoA to form cross-links has not yet been established experimentally, but it could be a substrate for one of the histone acyl transferases [50, 51] and so form amides via the CoA at one end and imines by its CHO group at the other, with amino groups on proteins. Chromatin cross-linking/condensation is one of the hall-marks of apoptosis [40]. Methional, MDA and other apoptogenic aldehydes like 4-hydroxy-2-nonenal are oxidized by ALDHs to non-apoptogenic carboxylic acids [29, 44, 45, 68] but retain their apoptotic activity when the ALDHs are inhibited [98, 110]. MASACoA would also lose its cross-linking capacity if its CoA moiety were putatively hydrolysed by ALDHs and/or acylCoA thioesterases [56, 58, 88, 89]. ALDH inhibitors that control cellular MDA and possibly MASACoA homeostasis are cited as examples of targeted therapeutic approaches in chemoresistant cancers [62, 84, 97, 98, 110].

Keywords: 4-methylthio-2-oxobutanoate (MTOB), methional, Aldehyde dehydrogenase inhibitors, bcl2-chemoresistant cancers, Acyl-CoA

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